Wu Shuai, Luo Weiwei, Wu Xing, Shen Zhaohua, Wang Xiaoyan
Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China.
Key Laboratory of Non-resolving Inflammation and Cancer of the Hunan Province, The Third Xiangya Hospital, Central South University, Changsha, China.
Front Med (Lausanne). 2022 May 9;9:840704. doi: 10.3389/fmed.2022.840704. eCollection 2022.
CXCL12 and its receptor CXCR4 are independent prognostic factors in colorectal cancer. AMD3100 is the most frequently used FDA-approved antagonist that targets the CXCL12-CXCR4 axis in clinical trials. We aimed to explore the role of AMD3100 and its effect on peritoneal macrophages' functional phenotypes during colitis-associated tumorigenesis. We treated AMD3100 in a colitis-associated colon cancer mouse model and evaluated its effect on tumorigenesis. The phagocytosis activities of peritoneal macrophages were measured by flow cytometry. The proportions of macrophages and M1/M2 subpopulations were investigated by flow cytometry, ELISA, and immunochemistry. Serum levels of pro-inflammatory and anti-inflammatory cytokines were measured by LEGENDplex™ kits. Transwell assay and qRT-PCR were performed to investigate the direct effect of CXCL12 on macrophages . We demonstrated that AMD3100 treatment reduced the inflammatory damages in the colonic mucosal and ameliorated tumor development in experimental mice. We found that the phagocytosis activities of peritoneal macrophages fluctuated during colitis-associated tumorigenesis. The proportions of peritoneal macrophages and M1/M2 subpopulations, together with their metabolite and cytokines, changed dynamically in the process. Moreover, AMD3100 regulated the functional phenotypes of macrophages, including reducing the recruiting activity, promoting polarization to the M1 subpopulation, and reducing IL-12 and IL-23 levels in serum. Our study contributes to understanding dynamic changes of peritoneal macrophages upon AMD3100 treatment during tumorigenesis and sheds light on the potential therapeutic target of AMD3100 and peritoneal macrophages against colitis-associated colon cancer.
CXCL12及其受体CXCR4是结直肠癌的独立预后因素。AMD3100是美国食品药品监督管理局（FDA）批准的、在临床试验中最常使用的靶向CXCL12-CXCR4轴的拮抗剂。我们旨在探讨AMD3100在结肠炎相关肿瘤发生过程中的作用及其对腹膜巨噬细胞功能表型的影响。我们在结肠炎相关结肠癌小鼠模型中使用AMD3100进行治疗，并评估其对肿瘤发生的影响。通过流式细胞术检测腹膜巨噬细胞的吞噬活性。通过流式细胞术、酶联免疫吸附测定（ELISA）和免疫化学研究巨噬细胞以及M1/M2亚群的比例。使用LEGENDplex™试剂盒检测促炎和抗炎细胞因子的血清水平。进行Transwell实验和定量逆转录聚合酶链反应（qRT-PCR）以研究CXCL12对巨噬细胞的直接作用。我们证明，AMD3100治疗可减轻实验小鼠结肠黏膜的炎症损伤并改善肿瘤发展。我们发现，在结肠炎相关肿瘤发生过程中，腹膜巨噬细胞的吞噬活性会发生波动。在此过程中，腹膜巨噬细胞以及M1/M2亚群的比例及其代谢产物和细胞因子均发生动态变化。此外，AMD3100可调节巨噬细胞的功能表型，包括降低募集活性、促进向M1亚群极化以及降低血清中白细胞介素-12（IL-12）和白细胞介素-23（IL-23）的水平。我们的研究有助于了解AMD3100治疗在肿瘤发生过程中对腹膜巨噬细胞的动态变化，并揭示了AMD3100和腹膜巨噬细胞针对结肠炎相关结肠癌的潜在治疗靶点。
